Spinal cord injury (SCI) often damages not only white matter axon tracts that carry signals to and from the brain, but also the central gray matter, causing segmental losses of interneurons and motor neurons. Transplantation of neural stem cells or neural progenitors not only potentially replaces lost neurons and glia, but could also serve as a functional relay between spinal cord segments that are disconnected by injury. Our preliminary data provide strong support for this functional relay hypothesis, showing grafted embryonic neurons support formation of functional electrophysiological relays across sites of complete spinal transection, resulting in behavioral recovery; spinal re- transection abolished all recovery. The proposed studies will determine whether extrinsic neurotrophins promote host supraspinal axon regeneration and re-innervation of grafted embryonic neurons to further strengthen formation of functional relays after SCI. In addition, we will examine mechanisms underlying functional relay formation and identify genes responsible for corticospinal tract axonal regeneration, using BAC-TRAP translational profiling. Lastly, we will transfer advances from rat embryonic spinal cord neuronal progenitor work to human embryonic stem (ES) cell approaches. This work will reveal whether extrinsic stimulation of neural systems after SCI can enhance supraspinal axonal regeneration and form graft-mediated neuronal relays that facilitate functional recovery. Further, this model system will provide a rich opportunity for identifying molecular mechanisms underlying axonal regeneration. The goals of this research are directly and highly relevant to the VA patient care mission. PUBLIC HEALTH RELEVANCE: Spinal Cord Injury (SCI) is damage to the spinal cord that results in permanent loss of function such as mobility or feeling below injury. There are approximately 250,000 Americans living with spinal cord injuries, and approximately 20,000 of those injured are veterans (data from Paralyzed Veterans of America). The number of such injuries is increasing as a result of the Iraq and Afghanistan war. Thus, care and treatment of spinal cord injured veterans is important to the VA patient care mission. The use of neural stem cells or progenitors as a functional relay is a very promised experimental study. Results from the current proposal will provide important knowledge that could form the basis for generating future therapies for acute and chronic SCI.